We could be just months away from knowing whether Depo-Provera use is linked to a higher risk of HIV infection in women.
For more than a decade, obstetrician Coceka Mnyani’s conversations with her patients followed a script.
Had they used contraceptives before? Did they want more children? What contraceptive did they plan on using after delivery and why?
“Depending on what a woman said, you would advise, you know, ‘that’s not such a great idea, have you thought about this’, ‘maybe this one would be a better option’,” Mnyani says.
“You’ve got this woman who has just had a baby, who’s tired, who has a crying infant — is she going to remember to take a pill every day?”
Health department data shows that most South African women visiting a public health facility for free contraception will leave with a shot of the three-month contraception depo-medroxyprogesterone acetate, which is most commonly sold under the name Depo-Provera. The contraception prevents unwanted pregnancies by using a synthetic form of the hormone progesterone to prevent women’s ovaries from releasing eggs every month.
Mnyani had always advised her patients on Depo to use condoms as well. The injection could protect them from pregnancy, but not sexually transmitted infections, including HIV, she warned.
Sitting across from a private doctor in central Johannesburg, Amahle Ndwandwa* insisted on Depo.
She had already had one unplanned pregnancy in her early 20s, and condoms could burst. She wanted a back-up.
But as a single mom working fulltime in a job that could take her out of town at short notice, she also needed something low-maintenance.
“I just wanted something that was proven to be quite effective, but that wouldn’t take too much of my time,” Ndwandwa, now 37, says.
When her doctor told her about Depo and how she’d only need to come in for a jab every three months, she jumped at it.
The important thing, he reminded her, was to use a condom anyway. “Which is something I already knew, but he felt compelled to tell me,” she explains.
“It really suited my lifestyle.” In South Africa, almost 60% of women in their reproductive years use contraceptives, according to the 2016 Demographic and Health Survey. Nearly one in five opt for an injectable method including Depo-Provera.
But there could be a catch to the country’s most popular birth control method. It could increase your risk of contracting HIV.
For more than a quarter of a century, scientists have wondered whether one of the world’s most widely used contraceptives could be helping to fuel HIV infections among young women. Several studies from countries including Zimbabwe, Kenya and South Africa have suggested that women who use the shot are at a 20% to 60% increased risk of contracting HIV compared with women not using hormonal contraception, according to a 2016 research review published in the journal Aids.
But no study yet has proved a definitive link. Why not?
Because the studies weren’t designed to find one. Scientists couldn’t tell whether it was the shot that was behind higher HIV infection rates in some studies or whether it was another factor — such as the lower rates of condom use 2005 research by the Guttmacher Institute picked up among some Depo users.
Then, in 2016, a clue emerged.
Researchers at the Centre for the Aids Programme of Research in South Africa (Caprisa) found that the shot was associated with weaker immune responses, at a cellular level, to infections in women’s vaginas. Caprisa research associate Sinaye Ngcapu told Bhekisisa in 2016.
“These responses may be crucial to protecting against HIV infection,” he explained.
Depo-Provera use was also associated with the increased presence of CD4 cells in women’s vaginas, Caprisa’s study showed. These cells are easily infected by HIV, meaning the shot could be changing the ecosystem of women’s reproductive tracts, making them more susceptible to HIV infection.
In a country where the latest household survey shows that a third of new HIV infections are among young women aged 15 to 24 — a group in which about one in two women on contraception opt for Depo, this was serious.
Again, the work couldn’t prove a definitive link between Depo and HIV infection, but it did help prompt the World Health Organisation (WHO) to review the evidence on the contraception’s possible HIV risk in December 2016.
Less than four months later, the WHO flipped the family planning script for doctors like Mnyani.
Before March 2017, the WHO had advised nurses and doctors that Depo could be used safely by anyone as long as they knew about the potential — as yet unproven — risk of HIV infection.
But the WHO found that this hadn’t always filtered down to women in conversations with their doctors. Now, the body was putting out more strongly worded advice, HIV prevention organisation Avac explained shortly after the announcement: for most, it works well enough but for some people it may be risky.
‘If there was a product that men were using that had a question like this hanging over it, we would have had an answer by now,” executive director of the Wits Reproductive Health and HIV Institute Helen Rees says.
Rees is helping to lead the first study specifically designed to prove whether or not Depo increases a woman’s risk of contracting HIV — the Evidence for Contraceptive Options and HIV Outcomes (Echo) trial.
The study is a randomised clinical trial, the gold standard for scientific research. This means that each of the 7 830 HIV-negative women participating in the study will be randomly assigned to take one of three contraceptives: Depo, a hormonal contraceptive upper-arm implant called Jadelle that can last up to five years or a small copper intrauterine device.
Because women are randomly assigned to these groups, other factors — such as low condom use — that could impact on their HIV infection risk should be spread evenly among the three clusters. This means these characteristics won’t be able to explain any potential differences in HIV infections scientists pick up among the women as they monitor them for up to 18 months.
Before taking part in the study, women were counselled about the trial’s risks and benefits, as well as how to prevent HIV infection with the use of condoms and even the HIV prevention pill in areas where it’s available from government providers, researchers explained in a peer-reviewed paper on the Gates Open Research site. The site allows free access to results from work funded by the Bill & Melinda Gates Foundation.
The study is taking place at 12 sites across four countries — South Africa, Swaziland, Zambia and Kenya — and results are expected in mid-2019.
Until recently, many didn’t think the world would ever see this kind of trial and doubts scared off funding for years.
Donors questioned whether designing a study in which women would have to agree to be randomly assigned a method of contraception was possible, Rees says.
“The question was, well, what if the women chop and change their method of contraception? What if the women disappear?”
Women in the Echo trial are encouraged to remain on their assigned contraception for the duration of the study but they can change methods at any time.
Particularly difficult was the ethical question: How could a trial justify giving participants a contraceptive method that might put them at increased risk of contracting HIV?
Rees argued that, as long as there was a question mark around Depo, it was unethical not to do the study.
“The uncertainty we’ve got continues to worry policymakers, healthcare providers and women. Bottom line: you’re in a busy clinic, you’re a nurse and a young woman comes in. What do you say to her? ‘There is a risk’, or ‘there might be a risk’? That’s a very hard counselling message,” she explained.
“This question’s been unanswered for nearly 30 years. We just felt that the ethics called for it to be answered once and for all. If there is a risk, women can be properly informed. If there isn’t, we can reassure everybody.”
Echo is due to release its results in mid-2019. Until then, governments and activists are preparing for how best to respond if the study finds that Depo does indeed increase the risk of HIV infection.
“We need to be sure that, when we open the envelope and there’s a research result, we know what to do with it,” Avac executive director Mitchell Warren says.
“Thinking about that a year from now is a year too late. It’s making sure people are ready to have those conversations today.”
If the link is there, South Africa will have to switch women to other methods of contraception rapidly, national health department deputy director general Yogan Pillay says.
“We’re already talking to suppliers in case we have to rapidly increase supply [of other methods].”
Historically, contraception options for South African women in the public sector have been limited.
Hanlie Cloete* was given two options: Depo or the pill.
“I said the pill was definitely out because I wouldn’t remember to take it,” Cloete, now 42, remembers. Depo, however, could make her heavy periods disappear. No periods?
Cloete, a climber and swimmer, opted in.
“That was the extent of the counselling … in all my conversations with doctors subsequently, it was always that: either Depo or the pill, and later the implant. Those were the only options that were explained to me.”
Since 2012, the South African government has tried to increase the number and kinds of contraception it offers — injectables, pills, implants, condoms, IUDs, vaginal rings, sterilisation.
But not much has changed for many South African women. In reality, “it’s a very limited basket,” HIV activist Yvette Raphael says. Raphael has conducted workshops on reproductive health across the country.
“Depo is punted as a choice for women — the preferred choice. But when we talk with women, it’s like, ‘no, we get offered Depo, we don’t choose it’,” she explains.
“It’s easier for the healthcare worker. If she takes 100 women and puts them on Depo, she only has to see them in another three months.”
And despite years of caution from the WHO, Raphael says the workshops are also often the first time many women hear about the possible link between the injection and acquisition of HIV.
“Women in South Africa do not get proper counselling in clinics. One of the reasons is long queues — the number of people the healthcare worker has to deal with. But that’s not an excuse.”
Pillay doesn’t necessarily agree that women are being coerced into using Depo.
“It sounds like it could happen, but there’s no empirical evidence to say that it does,” he argues.
Meanwhile, the health department has begun training and retraining health workers on how to provide contraceptive counselling to patients, Pillay says.
“We haven’t done enough to empower women to demand they be fully counselled on all their options when they visit a clinic. Informing women can’t be a one-off thing.”
Providing people, especially young women, with access to comprehensive sexual and reproductive health care including a range of contraception is also a goal of the country’s current HIV and TB plan. The strategy hopes to cut new HIV infections nationally by more than half by 2022.
Even if a causal link is found, Warren argues that keeping Depo in the mix of options available to women is important.
“Depo is a critical contraceptive method in a number of countries,” he says.
In countries like these, banning Depo without a replacement would lead to more unplanned and unwanted pregnancies — and more maternal deaths, a 2017 study published in the journal Global Health: Science and Practice found.
“I don’t think anybody responsibly should say we should get rid of Depo,” Warren cautions.
The shot is the right choice for some women, some of the time — not least for women already living with HIV or TB and whose treatment may interfere with other types of contraception, national contraception guidelines warn.
“What we really want to be focusing on, what we should always be focusing on, is making sure that the woman using the contraceptive has a much greater role in choosing it,” Warren argues. “A woman may say, ‘I’ve seen the evidence, and so I’d rather have the implant than Depo’ or ‘I see that Depo is increasing my risk but it’s the contraception that works for me — so I also want the [HIV prevention] pill so I can stay uninfected.”
He explains: “We choose things all the time for ourselves — do I want to wear a seatbelt? Do I want to have a cigarette? People need to be able to make those choices with clarity and certainty.”
Nearly two years since Echo began in earnest, the trial is beginning to wrap up.
There are no early indicators of what the results might be.
“I only know one thing with certainty with this trial and that is that there will be people a year from now who say ‘I told you so’,” Warren says.
“If Depo does increase HIV risk substantially, there will be people who say ‘I told you so, we’ve wasted three years, we’ve put women’s lives at risk,’” he says.
“If it doesn’t increase risk significantly, there will be people who say, ‘I told you so, we didn’t have to change anything.’”
“We don’t know which group of people it will be — and that’s why you do a clinical trial.”
* Not their real names